A dedicated skin-to-brain circuit for cool sensation in mice

Hankyu Lee, Chia Chun Hor, Lorraine R. Horwitz, Ailin Xiong, Xin-Yu Su, Daniel R. Soden, Sarah Yang, Wei Cai, Wenwen Zhang, Chen Li, Christopher Radcliff, Abbey Dinh, Tin Long Rex Fung, Ilma Rovcanin, Kevin P. Pipe, X. Z. Shawn Xu and Bo Duan ()
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Hankyu Lee: University of Michigan
Chia Chun Hor: University of Michigan
Lorraine R. Horwitz: University of Michigan
Ailin Xiong: University of Michigan
Xin-Yu Su: University of Michigan
Daniel R. Soden: University of Michigan
Sarah Yang: University of Michigan
Wei Cai: University of Michigan
Wenwen Zhang: University of Michigan
Chen Li: University of Michigan
Christopher Radcliff: University of Michigan
Abbey Dinh: University of Michigan
Tin Long Rex Fung: University of Michigan
Ilma Rovcanin: University of Michigan
Kevin P. Pipe: University of Michigan
X. Z. Shawn Xu: University of Michigan
Bo Duan: University of Michigan

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Perception of external temperature is essential for maintaining homeostasis and avoiding thermal injury. Although molecular thermosensors such as transient receptor potential melastatin type 8 (TRPM8) have been identified, the neural circuits responsible for transmitting cool signals remain unclear. Here we show that a spinal circuit in mice conveys cool signals from the skin to the brain. Excitatory interneurons in the spinal dorsal horn expressing thyrotropin-releasing hormone receptor (Trhr+) act as a central hub for cool sensation. These Trhr+ neurons receive monosynaptic input from TRPM8+ sensory afferents and are selectively activated by innocuous cool stimuli. Ablating Trhr+ interneurons abolishes behavioral responses to cool, but not to warm or cold stimuli. We also identify a population of calcitonin receptor-like receptor-positive (Calcrl+) spinal projection neurons that receive convergent input from both TRPM8+ afferents and Trhr+ interneurons, and transmit cool-specific signals to the lateral parabrachial nucleus (lPBN). Our findings define a feedforward amplification circuit for cool sensation and reveal a modality-specific spinal pathway for thermal processing.

Date: 2025
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DOI: 10.1038/s41467-025-61562-y

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